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Gastrointestinal stromal tumours

Abstract

Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 105 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.

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Fig. 1: Mutation prevalence in gastric, small intestine and rectal GIST.
Fig. 2: Driver mutations of molecular GIST subtypes.
Fig. 3: Signalling pathways of molecular GIST subtypes.
Fig. 4: Appearance of miniGIST.
Fig. 5: Histopathological features of gastric GIST.
Fig. 6: Histopathological features of molecular GIST subtypes.
Fig. 7: PDGFRA-mutated GIST.
Fig. 8: Management of localized and advanced or metastatic GIST.

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Acknowledgements

T.N. is supported by a Grant-in-Aid (19H03722) for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and by a Grant (31-A-14) from the National Cancer Center Research and Development Fund. J.-Y.B. holds grants from NetSARC (INCA & DGOS) and RREPS (INCA & DGOS), RESOS (INCA & DGOS), LYRICAN (INCA-DGOS-INSERM 12563), Association DAM’s, Eurosarc (FP7-278742), Fondation ARC, Infosarcome, InterSARC (INCA), LabEx DEvweCAN (ANR-10-LABX0061), PIA Institut Convergence François Rabelais PLAsCAN (PLASCAN, 17-CONV-0002), La Ligue de L’Ain contre le Cancer, La Ligue contre le Cancer, and EURACAN (EC 739521), RHU4 DEPGYN (ANR-18-RHUS-0009).

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Introduction (J.-Y.B.); Epidemiology (J.-Y.B.); Mechanisms/pathophysiology (T.N.); Diagnosis, screening and prevention (Y.-K.K., T.N., M.v.M.); Management (Y.-K.K., T.N., M.v.M.); Quality of life (J.-Y.B.); Outlook (J.-Y.B., Y.-K.K., T.N., M.v.M.).

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Correspondence to Jean-Yves Blay.

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Competing interests

J.-Y.B.: research support and honoraria from Novartis, GSK, Bayer, Roche, Deciphera and Ignyta. T.N.: honoraria from Pfizer, Novartis, Bayer, Taiho, Eli Lilly outside the submitted work. M.V.M.: honoraria from Deciphera, Blueprint, Exelexis; research support from Novartis. Y.-K.K. declares no competing interests.

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Blay, JY., Kang, YK., Nishida, T. et al. Gastrointestinal stromal tumours. Nat Rev Dis Primers 7, 22 (2021). https://doi.org/10.1038/s41572-021-00254-5

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